SUMMARY / ABSTRACT This is a 1st competitive renewal of our project ?Biophysical Basis of Resting State Connectivity by MRI?. Our goals are to determine whether inter-regional correlations in resting state fluctuations of MRI (rsfMRI) signals from the brain reliably measure functional connectivity (rsFC) between brain regions, and to establish how MRI data correlate with other metrics of connectivity. These goals are directly relevant for the validation and interpretation of human applications of rsfMRI. Studies performed to date have focused on mesoscopic scale networks (100m - 10mm) within a well defined functional region of primary somatosensory cortex (S1) in non-human primates, where we can measure spatial patterns of resting state correlations at high resolution and validate their interpretation with electrophysiological signals and anatomic tracers. In the next phase, we aim to expand these studies to further establish the origins and significance of rsFC measurements. Cerebral cortex exhibits a laminar structure, but the laminar distribution of rsFC is poorly understood. In addition, whether the strong inference that rsfMRI correlations directly represent and link functional connectivity extends beyond the fine-grained level of sub-regions in S1 to more macroscopic dimensions remains unexplored. Moreover, recent studies of apparent slow variations of rsfMRI correlations suggest that the resting state itself exhibits dynamic variations that may be of functional importance. We therefore propose three specific aims: [1] to identify the origins of rsFC by measuring the connectivity patterns of rsfMRI signals across and between cortical layers in sub-regions of S1, S2, thalamus and corresponding contralateral regions. We will acquire fMRI data at 9.4T using vibrotactile stimuli to identify functionally distinct candidate areas of activation in bilateral S1, S2, and thalamus, and measure resting state correlations between voxels within and across layers in these regions: [2] to measure the effects of selective deprivation of spinal, thalamic, cortical and inter-hemispheric inputs on rsfMRI and demonstrate their relationships to behavior: [3] to validate measurements of rsFC signals in normal and input-deprived conditions by direct comparisons with quantitative intracranial electrophysiology and histology. We will acquire rsfMRI and invasive multi-electrode measurements in the same animals to quantitatively compare different metrics of neural activity and anatomical connections. We will acquire fMRI data at 9.4T from monkey brain to study functionally distinct areas in SI, SII, and thalamus. We will use innovative mathematical analyses to quantify variations in resting state correlations across time and whether these patterns agree with slow variations in electrophysiological correlations. We will perform invasive multichannel microelectrode array measurements in the same animals so that we can quantitatively compare different metrics of neural activity and anatomical connections. We believe that the proposed studies have considerable importance for validating the neural basis of resting state functional connectivity measures, and have direct implications for human fMRI studies and their applications.